The acronym PHACES is used to describe the association of Posterior fossa malformations, Hemangiomas, Arterial anomalies (cardiovascular or cerebrovascular), Coarctation of the aorta and cardiac defects, Eye abnormalities, and Sternal or ventral defects. We studied a female patient with an uncommon variant of this neurocutaneous disorder who manifested a sternal cleft, supraumbilical raphe, hemangiomas of the face, chest, and extremities, micrognathia and cerebrovascular anomalies. A literature review of PHACES patients with both sternal cleft and supraumbilical raphe revealed a marked female predilection. Taken together with cases of sternal cleft, supraumbilical raphe and facial hemangiomas compiled in the literature, 91% (40/44) of patients are female. One affected male died shortly after birth. We hypothesized that the gender bias in PHACES results from mutation in a X-linked dominant gene often lethal in males, and performed X-inactivation analysis of the polymorphic androgen receptor locus in this family. We documented consistently skewed X-inactivation (80%/20% in two independent analyses) in the unaffected mother and consistently random X-inactivation (47:53 and 61:39 in independent analyses) in the proband. These findings are consistent with favorably skewed X-inactivation producing a normal maternal phenotype, a phenomenon documented in X-linked dominant Rett syndrome. Our future efforts will depend on ascertainment of other PHACES families in whom maternal X-inactivation studies can be pursued, and application of X-chromosome specific array-comparative genomic hybridization (array-CGH) experiments to search for submicroscopic copy number changes in PHACES syndrome patients.